Project Summary Ischemic stroke is the leading cause of long-term disability and is responsible for an estimated 5% of deaths worldwide, with an estimated 15% of incidences attributed to thromboembolism emanating from vulnerable carotid artery plaques. Carotid plaque risk is stratified based on luminal narrowing (stenosis) measured by ultrasound, but stenosis does not directly inform plaque stability. Stenosis based grading results in carotid revascularizations performed on patients with stable plaque, while opportunities for intervention are missed on patients bearing vulnerable plaque but sub-threshold stenosis. Thus, technology to accurately characterize plaque composition (i.e. fibrin content) is sorely needed to impact the risk/benefit of revascularization. Plaque vulnerability is heightened by prior rupture, intraplaque hemorrhage, or plaque erosion, all of which are associated with the presence of fibrin. Direct non-invasive detection of fibrin could provide powerful information about plaque composition and stability that is currently lacking in standard practice. Fibrin is a specific target for carotid disease because it is only present in advanced, vulnerable Stage VI plaques or in thrombus, but is not present in stable plaques, normal vessel wall or circulating blood. Molecular imaging of fibrin using fibrin-specific probes has been achieved in human clinical trials using magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT). However these are all expensive techniques, not well suited for screening. Newly emergent magnetic particle detection technology represents a low-cost, portable, and easy to operate alterative. Magnetic particle detection uses low cost, shelf-stable superparamagnetic iron-oxide nanoparticles (SPIONs) which can be detected at picomolar sensitivity with little to no background signal. This Phase I SBIR proposal combines fibrin-binding peptide technology owned by Collagen Medical with new magnetic particle detector technology being developed at Massachusetts General Hospital to generate initial proof of concept data for a low-cost, portable, and easy-to-operate magnetic particle detection test for vulnerable carotid plaque. We will conjugate our proprietary fibrin-specific peptides to SPIONs to create fibrin-targeted nanoparticles and then quantify their fibrin affinity, detection sensitivity, and stability in vitro. Concurrently we will develop a prototype magnetic particle detector designed for use in human carotid artery disease. We will select a lead candidate with high fibrin affinity and stability and use it to quantify the detection sensitivity of the magnetic particle detector. We will then demonstrate the ability and sensitivity to detect decreasing concentrations of magnetic particles in fibrin gels using an anthropomorphic phantom that simulates a fibrin-presenting carotid artery plaque.